Optical signal detection modules and methods

ABSTRACT

An apparatus for detecting an optical signal emissions includes signal transmission fibers. Each fiber includes cores having the same spatial core arrangement at each end. The first ends are configured to be optically coupled to the signal emission sources. Each fiber is configured to transmit an optical signal between the first end and the second. The apparatus can also include a frame assembly securing the first ends of the fibers in a first spatial fiber arrangement corresponding to a spatial arrangement of the signal emission sources. The frame assembly can also secure the second ends of the fibers in a second spatial fiber arrangement different from the first spatial fiber arrangement. The apparatus can also include at least one signal detector configured to be optically coupled to the second ends of the fibers, and configured to detect an optical signal emitted by each signal emission source.

BACKGROUND Field

This disclosure relates to apparatuses and methods for detecting opticalsignals emitted by signal emission sources.

Background

A sample assay instrument can perform assays on samples to determine thepresence or amounts of particular analytes in the samples. The analytescan include for example, biological antigens, cell or geneticabnormalities, or disease-associated pathogens in an organism orbiological sample. These assays can use probes to identify the desiredanalytes. Probes may include, for example, labels such as radiolabels,fluorophores or fluorescent dyes, biotins, enzymes, or chemiluminescentcompounds that emit a detectable signal.

To detect different analytes, different probes that emit detectiblydifferent signals can be used. For example, different probes configuredto detect different analytes can be formulated with fluorophores thatfluoresce at a respective predetermined wavelength when exposed to arespective excitation wavelength. Assays for detecting differentanalytes can be performed in parallel by alternately exposing the sampleto different excitation wavelengths and detecting the level offluorescence at the wavelength of interest that corresponds to the probefor each analyte. Parallel processing can be performed using differentsignal detecting modules configured to generate excitation signals ofdifferent wavelengths, and to measure emission signals of differentwavelengths. The strength of the emitted optical signal can beproportional to the amount of the analyte present in the sample.Accordingly, by periodically measuring, a signal indicative of thepresence and growth of the analyte can be detected.

BRIEF SUMMARY

In some embodiments, an apparatus for detecting an optical signalemission from a plurality of potential signal emission sources includesa plurality of signal transmission fibers. Each fiber can include aplurality of cores having a first spatial core arrangement at a firstend, and a second spatial core arrangement at a second end that is thesame as the first spatial arrangement. The first ends are configured tobe optically coupled to the plurality of potential signal emissionsources. Each fiber is configured to transmit an optical signal betweenthe first end and the second. The apparatus can also include a frameassembly securing the first ends of the plurality of signal transmissionfibers in a first spatial fiber arrangement corresponding to a spatialarrangement of the signal emission sources. The frame assembly can alsosecure the second ends of the plurality of signal transmission fibers ina second spatial fiber arrangement different from the first spatialfiber arrangement. The apparatus can also include at least one signaldetector configured to be optically coupled to the second end of eachsignal transmission fiber, and configured to detect an optical signalemitted by each signal emission source.

In some embodiments, the at least one signal detector comprises aplurality of signal detectors, and each signal detector is configured togenerate an excitation signal of a different predetermined excitationwavelength and to detect an emission signal of a different predeterminedemission wavelength. The apparatus can include a signal detectorcarrier, and the plurality of signal detectors can be mounted to thesignal detector carrier. The signal detector carrier is configured tomove such that each signal detector is sequentially optically coupled tothe second ends of the signal transmission fibers.

The first spatial fiber arrangement is rectangular and includes two ormore rows. Each row can include two or more of the first ends of thesignal transmission fibers.

The second spatial fiber arrangement can include one of (a) one or morecircles each comprising a plurality of second ends of the plurality ofsignal transmission fibers, and (b) one or more bundles of a pluralityof second ends of the plurality of signal transmission fibers. Thesignal detector carrier can include a rotatable carousel configured tomove the one or more signal detectors along a path corresponding to theone or more circles of the second spatial fiber arrangement.

The frame assembly can include an interface plate securing the firstends of the signal transmission fibers in the first spatial fiberarrangement, and a base, spaced apart from the interface plate, securingthe second ends of the signal transmission fibers in the second spatialfiber arrangement. The frame assembly can also include heat dissipatingfins extending from the interface plate.

The apparatus can also include a plurality of signal coupling elements,each being operatively disposed with respect to the respective first endof each signal transmission fiber.

A minimum bend radius of the plurality of signal transmission fibers isequal to or less than about 10 mm. For example, the minimum bend radiusof the plurality of signal transmission fibers is equal to or less thanabout 5 mm.

In some embodiments, a method of diagnosing an optical misalignmentbetween a signal detector and a first end of signal transmission fiberincludes emitting an optical signal from the signal detector. The methodfurther includes transmitting the emitted optical signal from the firstend of the signal transmission fiber to a second end the signaltransmission fiber, and determining whether an intensity pattern of thetransmitted optical signal at the second end is symmetric or asymmetric.A symmetric intensity pattern indicates that the signal detector and thefirst end of signal transmission fiber are optically aligned, and anasymmetric intensity pattern indicates that the signal detector and thefirst end of the signal transmission fiber are optically misaligned.

In some embodiments, the determining step is manual. For example, thedetermining step can include visually inspecting the second end of thesignal transmission fiber. The visually inspecting step can includeusing a magnifier that generates a magnified image of the second end ofthe signal transmission fiber. The magnifier can include a magnifyingglass, or a camera system having a camera that acquires an image of thesecond end of the signal transmission fiber, and a display that displaysa magnified image based on the acquired image of the second end of thesignal transmission fiber.

In some embodiments, the determining step is automatic. For example, thedetermining step can include generating an image of the second end ofthe signal transmission fiber, and automatically analyzing the generatedimage to determine whether the intensity pattern of the transmittedoptical signal at the second end is symmetric or asymmetric.

In some embodiments, the method also includes, when the intensitypattern of the transmitted optical signal at the second end isasymmetric, adjusting the relative position between the signal detectorand the first end of the signal transmission fiber. The magnitude anddirection of the relative position adjustment between the signaldetector and the first end of the signal transmission fiber can bedetermined based on the intensity pattern of the transmitted opticalsignal.

The emitting, transmitting, and determining steps can occur during themanufacturing of a sample assay instrument comprising the signaldetector and the signal transmission fiber. Or the emitting,transmitting, and determining steps can occur during routine maintenanceof a sample assay instrument comprising the signal detector and thesignal transmission fiber, or while trouble shooting a problem with thesample assay instrument after being manufactured.

Further features and advantages of the embodiments, as well as thestructure and operational of various embodiments, are described indetail below with reference to the accompanying drawings. It is notedthat the invention is not limited to the specific embodiments describedherein. Such embodiments are presented herein for illustrative purposesonly. Additional embodiments will be apparent to persons skilled in therelevant art(s) based on the teachings contained herein.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated herein and form partof the specification, illustrate the present disclosure and, togetherwith the description, further serve to explain the principles of thedisclosure.

FIG. 1 is a perspective view of a signal detection module, according toan embodiment.

FIG. 2 is a cross-sectional view of a signal transmission fiber,according to an embodiment.

FIG. 3 is a front perspective view of a signal detection module,according to an embodiment.

FIG. 4 is a rear perspective view of the signal detection module shownin FIG. 3 , according to an embodiment.

FIG. 5 is a cross-sectional view of the signal detection module alongthe line 5-5 in FIG. 3 , according to an embodiment.

FIG. 6 is a front perspective view of a frame assembly of the signaldetection module shown in FIGS. 3-5 , according to an embodiment.

FIG. 7 is a rear perspective view of the frame assembly shown in FIG. 6, according to an embodiment.

FIG. 8 is a top perspective view of a frame assembly, according to anembodiment.

FIG. 9 shows the fiber position mapping at an interface plate of theframe assembly shown in FIG. 8 , according to an embodiment.

FIG. 10 shows the fiber position mapping at a baseplate of the frameassembly shown in FIGS. 8 and 9 , according to an embodiment.

FIG. 11 is a table showing the mapping between the fiber positions atthe interface plate and the fiber positions at the base of a frameassembly, according to an embodiment.

FIG. 12 is a front perspective of a frame assembly, according to anembodiment.

FIG. 13 is a perspective view of a signal detector head, according to anembodiment.

FIG. 14 is a cross-sectional view of the signal detector head along theline 14-14 in FIG. 13 , according to an embodiment.

FIG. 15 is a schematic diagram of an exemplary optical path within asignal detector, according to an embodiment.

FIG. 16 is a schematic diagram of a signal detection module, accordingto an embodiment.

FIG. 17 is a schematic diagram of a control system for a signal detectorhead, according to an embodiment.

FIG. 18 is a perspective view of a signal detector head, according to anembodiment.

FIG. 19 is a cross-sectional view of the signal detector head of FIG. 18, according to an embodiment.

FIG. 20 is an image of a second end of the signal transmission fiberhaving a symmetric intensity pattern, according to an embodiment.

FIG. 21 is an image of a second end of the signal transmission fiberhaving an asymmetric intensity pattern, according to an embodiment.

The features and advantages of the embodiments will become more apparentfrom the detailed description set forth below when taken in conjunctionwith the drawings, in which similar reference characters identifycorresponding elements throughout.

DETAILED DESCRIPTION

Reference will now be made in detail to examples of the presentdisclosure, which are illustrated in the accompanying drawings. Whereverpossible, the same or similar reference numbers will be used throughoutthe drawings to refer to the same or like parts. Although embodiments ofthe current disclosure are described with reference to its applicationin an instrument that performs molecular genetics related sampleanalysis, this is only exemplary. As a person skilled in the art wouldrecognize, embodiments of the current disclosure may be applied to anyapplication.

Unless defined otherwise, all terms of art, notations and otherscientific terms/terminology used herein have the same meaning as iscommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. All patents, applications, published applicationsand other publications (literature) referred to herein are incorporatedby reference in their entirety. If a definition set forth in thissection is contrary to or otherwise inconsistent with a definition setforth in the literature incorporated herein by reference, the definitionset forth in this section prevails over the definition that isincorporated by reference.

References in the specification to “one embodiment,” “an embodiment,” a“further embodiment,” “an example embodiment,” “some aspects,” “afurther aspect,” “aspects,” “for example,” “exemplary,” “someembodiments,” etc., indicate that the embodiment described may include aparticular feature, structure, or characteristic, but every embodimentmay not necessarily include the particular feature, structure, orcharacteristic. Moreover, such phrases are not necessarily referring tothe same embodiment. Further, when a particular feature, structure, orcharacteristic is described in connection with an embodiment, suchfeature, structure, or characteristic is also a description inconnection with other embodiments whether or not explicitly described.Further, as used herein, “a” or “an” means “at least one” or “one ormore.”

Further, the description below may use relative spatial and/ororientation terms in describing the position and/or orientation of acomponent, apparatus, location, feature, or a portion thereof. Unlessspecifically stated, or otherwise dictated by the context of thedescription, such terms, including, without limitation, top, bottom,above, below, under, on top of, upper, lower, left of, right of, inside,outside, inner, outer, proximal, distal, in front of, behind, next to,adjacent, between, horizontal, vertical, diagonal, longitudinal,transverse, etc., are used for convenience in referring to suchcomponent, apparatus, location, feature, or a portion thereof in thedrawings and are not intended to be limiting.

As used herein, a “sample assay instrument” refers to any instrumentcapable of performing an assay on a sample and rendering a result. Forexample, a sample assay instrument includes any diagnostic instrumentcapable performing an assay on a sample to determine the presence of ananalyte in the sample. Any diagnostic instrument capable of performing ahybridization assay, a molecular assay including a nucleic-acid-basedamplification reaction, a sequencing assay, an immunoassay, or chemistryassay on a sample is included in this definition of a sample assayinstrument. Exemplary diagnostic instruments capable performing an assayon a sample to determine the presence of an analyte in the sampleinclude the Tigris®, Panther®, and Panther Fusion® systems sold byHologic, Inc., Marlborough, Mass., as well as any of the diagnosticinstruments disclosed in U.S. Patent Application Publication No.2016/0060680, published Mar. 3, 2016.

As used herein, a “sample” refers to any material to be analyzed,regardless of the source. The material can be in its native form or anystage of processing (e.g., the material can be chemically altered or itcan be one or more components of a sample that have been separatedand/or purified from one or more other components of the sample). Asample can be obtained from any source, including, but not limited to,an animal, environmental, food, industrial or water source. Animalsamples include, but are not limited to, peripheral blood, plasma,serum, bone marrow, urine, bile, mucus, phlegm, saliva, cerebrospinalfluid, stool, biopsy tissue including lymph nodes, respiratory tissue orexudates, gastrointestinal tissue, cervical swab samples, semen or otherbody or cellular fluids, tissues, or secretions. Samples can be dilutedor contained within a receptacle containing diluents, transport media,preservative solution, or other fluids. As such, the term “sample” isintended to encompass samples contained within a diluent, transportmedia, and/or preservative or other fluid intended to hold a sample.

Exemplary Sample Assay Instruments

In some embodiments, a sample assay instrument is configured to transmitand/or measure signals emitted by potential emission signal sources foruse during a nucleic acid diagnostic assays, for example, “real-time”amplification assays and “end-point” amplification assays. Exemplarynucleic acid diagnostic assay can include performing polymerase chainreactions (PCR), transcription-mediated amplification reactions (TMA),ligase chain reactions (LCR), strand displacement amplificationreactions (SDA), and loop-mediated isothermal amplification reactions.

In some embodiments, the sample assay instrument is configured toperform real-time implication assays. Real-time amplification assays canbe used to determine the presence and amount of a target nucleic acid ina sample. The target nucleic acid can be, for example, derived from apathogenic organism or virus. By determining the quantity of a targetnucleic acid in a sample, a practitioner can approximate the amount orload of the organism or virus in the sample. In one application, areal-time amplification assay may be used to screen blood or bloodproducts intended for transfusion for bloodborne pathogens, such ashepatitis C virus (HCV) and human immunodeficiency virus (HIV). Inanother application, a real-time assay may be used to monitor theefficacy of a therapeutic regimen in a patient infected with apathogenic organism or virus, or that is afflicted with a diseasecharacterized by aberrant or mutant gene expression. Real-timeamplification assays may also be used for diagnostic purposes, as wellas in gene expression determinations.

In some embodiments, the sample assay instrument is configured toperform end-point amplification assays. In end-point amplificationassays, the presence of amplification products containing the targetsequence or its complement is determined at the conclusion of anamplification procedure. In contrast, the amount of amplificationproducts containing the target sequence or its complement is determinedduring a “real-time” amplification assays. In exemplary real-timeamplification assays, the concentration of a target nucleic acid can bedetermined using data acquired by making periodic measurements ofsignals that are functions of the amount of amplification product in thesample containing the target sequence, or its complement, andcalculating the rate at which the target sequence is being amplifiedfrom the acquired data.

In some exemplary real-time amplification assays, the probes can beunimolecular, self-hybridizing probes having a pair of interactinglabels that interact and thereby emit different signals, depending onwhether the probes are in a self-hybridized state or hybridized to thetarget sequence or its complement. Other probes, for example,complementary, bimolecular probes and probes labeled with anintercalating dye, can be used in some real-time amplificationembodiments. Exemplary interacting labels include enzyme/substrate,enzyme/cofactor, luminescent/quencher, luminescent/adduct, dye dimers,and Forrester energy transfer pairs.

The embodiments of the present disclosure operate regardless of theparticular labeling scheme utilized provided the moiety to be detectedcan be excited by a particular wavelength of light and emits adistinguishable emission spectra.

In some exemplary real-time amplification assays, interacting labels caninclude a fluorescent moiety, or other emission moiety, and a quenchermoiety, such as, for example, 4-(4-dimethylaminophenylazo)benzoic acid(DABCYL). The fluorescent moiety emits light energy (i.e., fluoresces)at a specific emission wavelength when excited by light energy at anappropriate excitation wavelength. When the fluorescent moiety and thequencher moiety are held in close proximity, light energy emitted by thefluorescent moiety is absorbed by the quencher moiety. But when a probehybridizes to a nucleic acid present in the sample, the fluorescent andquencher moieties are separated from each other, and light energyemitted by the fluorescent moiety can be detected. Fluorescent moietieshaving different and distinguishable excitation and emission wavelengthsare often combined with different probes. The different probes can beadded to a sample, and the presence and amount of target nucleic acidsassociated with each probe can be determined by alternately exposing thesample to light energy at different excitation wavelengths and measuringthe light emission from the sample at the different wavelengthscorresponding to the different fluorescent moieties. In anotherembodiment, different fluorescent moieties having the same excitationwavelength, but different and distinguishable emission wavelengths arecombined with different probes. The presence and amount of targetnucleic acids associated with each probe can be determined by exposingthe sample to a specific wavelength light energy and the light emissionfrom the sample at the different wavelengths corresponding to thedifferent fluorescent moieties is measured.

In one example of a multiplex, real-time amplification assay, thefollowing may be added to a sample prior to initiating the amplificationreaction: (1) a first probe having a quencher moiety and a firstfluorescent dye (having an excitation wavelength λ_(ex1) and emissionwavelength λ_(em1)) joined to its 5′ and 3′ ends and having specificityfor a nucleic acid sequence derived from HCV; a second probe having aquencher moiety and a second fluorescent dye (having an excitationwavelength λ_(ex2) and emission wavelength λ_(em2)) joined to its 5′ and3′ ends and having specificity for a nucleic acid sequence derived fromHIV Type 1 (HIV-1); and a third probe having a quencher moiety and athird fluorescent dye (having an excitation wavelength λ_(ex3) andemission wavelength λ_(em3)) joined to its 5′ and 3′ ends and havingspecificity for a nucleic acid sequence derived from West Nile virus(WNV). After combining the probes in a sample with amplificationreagents, the samples can be periodically and alternately exposed toexcitation light at wavelengths λ_(ex1), λ_(ex2), and λ_(ex3), and thenmeasured for emission light at wavelengths λ_(em1), λ_(em2), andλ_(em3), to detect the presence (or absence) and amount of all threeviruses in the single sample. The components of an amplification reagentwill depend on the assay to be performed, but can contain at least oneamplification oligonucleotide, such as a primer, a promoter-primer,and/or a promoter oligonucleotide, nucleoside triphosphates, andcofactors, such as magnesium ions, in a suitable buffer, according tosome embodiments.

In some multiplex embodiments, suitable dyes include rhodamine dyes(e.g., tetramethyl-6-rhodamine (“TAMRA”) andtetrapropano-6-carboxyrhodamine (“ROX”)) and fluorescein dyes (e.g.,6-carboxyfluorescein (“FAM”)) each in combination with a DABCYLquencher. In some embodiments, other suitable dyes include5′-hexachlorofluorescein phosphoramidite (“HEX”), and 2′,7′-dimethoxy-4′, 5′-dichloro-6-carboxyfluorescein (“JOE”), DyLight 647,and DyLight 677. Because the dyes are excited at different wavelengths,each signal detector can be tailored to emit an excitation light at ornear the desired excitation wavelength (i.e., color) for the particulardye that the fluorometer is intended to detect. Accordingly, componentselection for the detector/fluorometer will, in many instances, begoverned by the particular dye for which signal detector is intended.For example, the particular light source (e.g., the particular LED) usedwill depend on the dye for which the fluorometer is intended to detect.

Where an amplification procedure is used to increase the amount of atarget sequence, or its complement, present in a sample before detectionoccurs, a “control” can be included to ensure that amplification hastaken place. Such a control can be a known nucleic acid sequence that isunrelated to the sequence(s) of interest. A probe (i.e., a controlprobe) having specificity for the control sequence and having a uniquefluorescent dye (i.e., the control dye) and quencher combination can beadded to the sample, along with one or more amplification reagentsneeded to amplify the control sequence, as well as the targetsequence(s). After exposing the sample to appropriate amplificationconditions, the sample is alternately exposed to light energy atdifferent excitation wavelengths (including the excitation wavelengthfor the control dye) and emission light is detected. Detection ofemission light of a wavelength corresponding to the control dye confirmsthat the amplification was successful (i.e., the control sequence wasindeed amplified), and thus, any failure to detect emission lightcorresponding to the probe(s) of the target sequence(s) is not likelydue to a failed amplification. Conversely, failure to detect emissionlight from the control dye may be indicative of a failed amplification,thus calling into question the results from that assay. Alternatively,failure to detect emission light may be due to failure or deterioratedmechanical and/or electrical performance of an instrument (describedbelow) for detecting the emission light.

Apparatus and procedures embodying aspects of the disclosure may be useda variety of nucleic acid amplification procedures, including inconjunction with real-time PCR, which requires accurate/rapidthermocycling between denaturation (e.g., about 95° C.), annealing(e.g., about 55° C.), and synthesis (e.g., about 72° C.) temperatures.For this purpose, receptacles containing a reaction mixture for PCR areheld in a thermocycler configured to effect temperature cycling betweenthe denaturation, annealing, and synthesis phases. Emission signalmonitoring (e.g., of fluorescence) of the contents of the receptaclesheld in the thermocycler occurs at one or many color wavelengths duringeach temperature cycle between 95° C., 55° C., and synthesis 72° C.

One round of PCR synthesis will result in new strands of indeterminatelength which, like the parental strands, can hybridize to theamplification oligonucleotides upon denaturation and annealing. Theseproducts accumulate arithmetically with each subsequence cycle ofdenaturation, annealing to amplification oligonucleotides, andsynthesis. The second cycle of denaturation, annealing, and synthesisproduces two single-stranded products that together compose a discretedouble-stranded product which comprises the length between theamplification oligonucleotide ends. Each strand of this discrete productis complementary to one of the two amplification oligonucleotides andcan therefore participate as a template in subsequent cycles. The amountof this product doubles with every subsequent cycle of synthesis,denaturation and annealing. This accumulates exponentially so that 30cycles should result in a 2²⁸-fold (270 million-fold) amplification ofthe discrete product.

Exemplary Signal Detection Modules

Detection and, optionally, measurement of optical emission signals fromoptical emission signal sources, such as receptacles containing samplesundergoing amplification as described above can be performed with asignal detection module, in some embodiments. A signal detection moduleaccording to an embodiments is indicated by reference number 100 in FIG.1 . Signal detection module 100 can be part of a sample assay instrumentas described above.

Signal detection module 100 can include an frame assembly 102. Signaldetection module 100 can also include one or more, for example, two asshown in FIG. 1 , signal detector heads 104 that are attached to a lowerend of frame assembly 102. Frame assembly 102 can also include aninterface plate 106 that is attached to an upper end of frame assembly102. In some embodiments, frame assembly 102 includes two opposing sides108, 110. Sides 108, 110 can be generally vertical as shown in FIG. 1 .Frame assembly 102 can also include a base 112 attached to the bottomends of sides 108, 110. Base 112 can define a plurality offiber-positioning holes 114. Note that the designations that sides 108,110 are vertical is merely to provide a convenient reference withrespect to the orientation of signal detection module 100 as shown inFIG. 1 , and such term of orientation is not intended to be limiting.Accordingly, signal detection module 100 could be oriented at any angle,including vertical or horizontal, or any angle therebetween.

Frame assembly 102 can have a variety of purposes, including organizingand arranging a plurality of optical transmission fibers 116 that extendbetween an excitation/emission area and a detection area. In someembodiments, frame assembly 102 can arrange optical signal transmissionfibers in an optimum optical pathway orientation. In some embodiments,frame assembly 102 provides for controlled orientation of opticaltransmission fibers 116 between the fins of a heat sink to a detectionarea.

Optical transmission fibers 116 are optical signal transmission conduitsbetween interface plate 106 and base 112 of frame assembly 102. In someembodiments, each optical transmission fiber 116 is a multicore fiberhaving a plurality of flexible, transparent cores 118 that transmitlight between the two ends of the optical transmission fiber 116.Transparent cores 118 can be made of glass (silica) or polymer.

FIG. 2 illustrates a cross-section of an exemplary multicore opticalfiber 116 according to an embodiment. In some embodiments (as shown inFIG. 2 ), each core 118 includes an optical cladding 120 that encasescore 118, and a jacket 122 encases the plurality of cores 118, therebyforming optical transmission fiber 116.

In some embodiments, a diameter 124 of each core 118 ranges from about500 μm to about 2500μ. For example, diameter 124 can be about 1500 μm.In other embodiments, diameter 124 is less than about 500 μm or morethan about 2500 μm.

In some embodiments, a diameter 126 of the entire optical fiber 116ranges from about 1000 μm to about 3500 μm. For example, diameter 126can be about 2200 μm. In other embodiments, diameter 126 is less thanabout 1000 μm or more than about 3500 μm.

In some embodiments, each optical transmission fiber 116 includes atleast 10 cores 118. For example, as shown in FIG. 2 , opticaltransmission fiber 116 can include thirty-seven cores 118. In otherembodiments, optical transmission fiber 116 includes ten to thirty-sixcores 118 or more than thirty-seven cores 118.

In some polymer embodiments, each core 118 is made of polymethylmethacrylate (PMMA), also referred to as acrylic. In other polymerembodiments, cores 118 are made of any other suitable polymer.

In some embodiments, optical cladding 120 is made of any suitablefluorinated polymer. For example, cladding 120 can be made of an opaqueor transparent material having a lower index of refraction than thematerial composing cores 118. In some embodiments, cladding 120 is madeof a material that is resistant to the effects of high heat indexes—theoptical transmission properties of cores 118 are maintained in thepresence of heat indexes well-above room temperature.

In some embodiments, jacket 122 is made of polyethylene (PE) or anyother suitable polymer.

In some embodiments, the numerical aperture (NA) of each core 118 rangesfrom about 0.25 to about 0.75. In some embodiments, the numericalaperture is about 0.5. In other embodiments, the numerical aperture isless than about 0.25 or more than about 0.75.

In some embodiments, the attenuation of each optical transmission fiber116 is equal to or less than about 0.5 dB/m. For example, theattenuation is equal to or less than 0.45 dB/m. In other embodiments,the attenuation of each optical transmission fiber 116 is more than 0.5dB/m.

In some embodiments, the minimum bend radius of each opticaltransmission fiber 116 is equal to or less than about 15 mm. Forexample, the minimum bend radius can be about 10 mm or about 5 mm, orthe minimum bend radius is equal to or less than about 5 mm. In otherembodiments, the minimum bend radius is more than about 15 mm.

In some embodiments, the minimum bend radius ranges from about 1.75times to about 2.75 times the diameter 126 of optical transmission fiber116. For example, the bend radius can be about 2.25 times the diameter126 of optical transmission fiber 116. In other embodiments, the minimumbend radius is less than 1.75 times the diameter 126 or more than 2.75times the diameter 126.

In some embodiments, each core 118 can have a non-circularcross-section. For example, as shown in FIG. 2 , one or more of cores118 can have a substantially trapezoidal cross-sectional shape.Non-circular cross-sections can be achieved, for example, by placingcores 118 together at higher temperatures and under pressure during themanufacturing process of optical transmission fiber 116. In someembodiments, the non-circular cross-section minimizes the space betweenadjacent cores 118.

In some embodiments, the relative position of each core 118 at one endof fiber 116 is the same as the relative position of each core 118 atthe other end of fiber 116. That is, the spatial core arrangement at oneend of each fiber 116 is the same as the spatial core arrangement at theother end of fiber 116. In such embodiments, the spatial distribution ofoptical intensity of the light is not mixed or homogenized as the lighttravels from one end to the other of fibers 116.

In other embodiments (not shown), each core 118 has a circularcross-section.

In some embodiments, fibers 116 are configured to meet the backgroundfluorescence requirements for the fluorescent moieties, for example,fluorescing dyes, being used to perform assays with the sample assayinstrument. Background fluorescence is the light emitted by fibers 116,themselves, in response to transmitting the excitation optical signal.Background fluorescence can create problems if it has the samewavelength as the light emitted by the fluorescent moiety when excitedby the same excitation wavelength. Accordingly, in some embodiments,fibers 116 are configured such that magnitude (e.g., in relativefluorescence units (RFU)) of the background fluorescence of fibers 116at a particular emitted wavelength when excited by an excitationwavelength for a particular fluorescent moiety is below a predeterminedthreshold. In some embodiments, fibers 116 are also configured such thatmagnitude (e.g., in relative fluorescence units (RFU)) of the backgroundfluorescence of fibers 116 at a particular emitted wavelength whenexcited by an excitation wavelength for a particular fluorescent moietyused in an assay is also above a predetermined threshold. For example,in some embodiments, fibers 116 are configured such that the magnitudeof background fluorescence that corresponds to the respective emittedwavelengths for the following fluorescing dyes falls within thefollowing predetermined maximum and minimum thresholds:

FAM HEX ROX DY647 DY677 MAX. (RFU) 3500 400 200 750 750 MIN. (RFU) 50040 30 30 30

Turning back to FIG. 1 , frame assembly 102 is configured to reconfigureor reformat the relative spatial arrangements of optical transmissionfibers 116 at first ends relative to their second ends. In someembodiments, frame assembly 102 is configured to rearrange opticaltransmission fibers 116 into a spatial fiber arrangement in which theycan be more efficiently interrogated by a signal measuring device thatmeasure signals transmitted through each fiber 116. In the context ofthis description, the first end of a respective fiber 116 corresponds tothe end of fiber 116 closest to the signal emission source that is beingmeasured, and the second end of the respective fiber 116 corresponds tothe end of fiber 116 closest to the signal detector. The labels “first”and “second” ends is merely a convenient terminology for distinguishingone end of a respective transmission fiber 116 from another end of thetransmission fiber 116. Otherwise, the designation of the ends as beinga first end or a second end is arbitrary.

The first ends of transmission fibers 116 are attached to interfaceplate 106. For example, the first ends can extend into or through holes128 defined by interface plate 106. In some embodiments, signal couplingelements 130, e.g., ferrules or connectors, may be provided in each ofholes 128 defined by interface plate 106. Signal coupling elements 130are configured to securely attach each optical transmission fiber 116 tointerface plate 106. Although not shown in FIG. 1 , each hole 128 formedin interface plate 106 may be in signal transmission communication,i.e., optically coupled, with an emission signal source. In someembodiments, a signal emission source may comprise a receptaclecontaining the contents of a chemical or biological assay (e.g., asample). The receptacles may be positioned and held so as to opticallyisolate each receptacle from the surrounding receptacles. In addition,as noted above, the receptacles may be held within an incubator deviceconfigured to alter the temperature of receptacles or maintain thereceptacles at a specified temperature. In some embodiments, interfaceplate 106 can be made of a suitable heat-conducting material, such asaluminum or copper, and include a plurality of heat dissipating fins 132formed on one side of interface plate 106 for dissipating heat frominterface plate 106 by convection. In some embodiments, signal couplingelements 130 can thermally insulate optical transmission fibers 116 fromthe heat of the receptacles held within the incubator. An exemplaryinsulating material for signal coupling elements 130 includespolyethylene ketone (PEEK).

In some embodiments, optical transmission fibers 116 are attached tointerface plate 106 in a rectangular spatial arrangement comprising aplurality of rows, as shown in FIG. 1 . Each row can have one or moretransmission fibers 116. As shown in the illustrated embodiment,interface plate 106 can include heat dissipating fins 132, andtransmission fibers 116 may extend between adjacent fins 132 into anassociated hole 128 formed in interface plate 106. In the illustratedembodiment, interface plate 106 forms twelve rows of five transmissionfibers 116 each, for a total of sixty transmission fibers 116 that canbe employed for interrogating up to sixty individual emission sources(e.g., reaction receptacles containing reaction materials (e.g., asample) therein). Each row of transmission fibers 116 may be disposedbetween a pair of adjacent heat-dissipating fins 132.

The second ends of transmission fibers 116 are attached to base 112 offrame assembly 102. The second ends of transmission fibers 116 can be,for example, aligned with or inserted into or through fiber-positioningholes 114. Fiber-positioning holes 114 are spatially arrange differentlyfrom the spatial arrangement of fiber-receiving holes 128 formed ininterface plate 106. The spatial arrangement of fiber-positioning holes114 is configured to allow for efficient interrogation by one or moresignal detectors. In the illustrated embodiment, the fiber-positioningholes 114 for each signal detector head is arranged in a circle. Asshown in FIG. 1 , each circular spatial arrangement accommodates aplurality of transmission fibers 116 extending from interface plate 106.Other spatial arrangements are contemplated, including, two or moreconcentric circles, one or more open rectangles, one or more ovals, etc.

The length of the frame assembly 102 is defined by a distance betweenbase 112 and interface plate 106. In some embodiments, this length canbe based one or more competing design considerations. On one hand ismaking signal detection module 100 as compact as possible, whichincludes making the length of frame assembly 102 as small as possible.On the other hand, the flexibility of transmission fibers 116 is limitedby the minimum bend radius of fibers 116. A longer frame assembly 102will make it easier to bend each transmission fiber 116 whenreformatting the fibers from their spatial configuration at interfaceplate 106 to their spatial configuration at base 112. In one embodiment,when each circular arrangement includes thirty multicore fibers 116having a minimum bend radius of 5 mm or less, frame assembly 102 canhave a length that ranges from about 100 mm to about 300 mm. Forexample, the length of frame assembly 102 can be about 130 mm to about160 mm.

FIGS. 3-5 illustrate an alternative embodiment of a signal detectionmodule 300. Signal detection module 300 can include a frame assembly 302that includes sides 308, 310. Frame assembly 302 can also include a base312, and an interface plate 306 attached to one end of frame assembly302. Signal detection module 300 can also include two signal detectorheads 104 attached to base 312 at an end of frame assembly 302 oppositeof interface plate 306. As opposed to the embodiment shown in FIG. 1 ,in which base 112 of frame assembly 102 forms a generally orthogonalangle with respect to the sides 108, 110 of frame assembly 102 such thatbase 112 is generally parallel to interface plate 106, frame assembly302 of signal detection module 300 is configured such that base 312 isangled relative to interface plate 306 so that base 312 is not parallelto interface plate 306.

Optical transmission fibers 116 extend from a first end thereofconnected to interface plate 306 to a second end thereof connected tobase 312. Optical transmission fibers 116 at the first end have a firstspatial fiber arrangement, and have a second spatial fiber arrangement,different than the first spatial fiber arrangement, at the second end.As with the embodiment shown in FIG. 1 , transmission fibers 116 can bereformatted from a generally rectangular, multi-row arrangement atinterface plate 306 into two circular arrangements, each accommodatinghalf of transmission fibers 116, at base 312.

As also shown in FIGS. 3-5 , a processing module 334, such as anincubator (e.g., a thermocycler), is positioned above interface plate306. Processing module 334 can include a plurality of receptacle holders336, each configured to hold one or more receptacles 338. In theillustrated embodiment, receptacle holders 336 are configured tocollectively hold sixty receptacles 338 arranged in twelve rows of fivereceptacles 338 each. The arrangement of receptacle holders 336 (andreceptacles 338 supported thereby) corresponds to the spatialarrangement of the first ends of fibers 116 at interface plate 106.Accordingly, the first ends of fibers 116 can be optically coupled withreceptacles 338. In some embodiments, receptacle holders 336 areconfigured to collectively hold less than or more than sixty receptacles338. In some embodiments, processing module 334 may be an incubator, andeach receptacle holder 336 is configured to impart thermal energy toreceptacles 338 held thereby to change and/or maintain the temperatureof the contents of each receptacle 338.

For applications in which heat dissipation from interface plate 306 isnecessary or desirable, such as when the processing module 334 includesan incubator or other heat-generating device, heat dissipating fins 332may be provided on interface plate 306. To augment heat dissipation viaheat dissipating fins 332, signal detection module 300 may include a fan340 (shown in FIGS. 4 and 5 ) disposed within a fan housing 342 mountedto frame assembly 302. Fan 340 is configured to generate air flow overheat dissipating fins 332 to enhance the convective heat dissipationfrom fins 332.

FIGS. 6 and 7 show a front perspective view and a rear perspective view,respectively, of fiber frame assembly 302 of signal detection module 300shown in FIGS. 3-5 . Signal detector heads 104, processing module 334,fan 340, and fan housing 342 are not shown in FIGS. 6 and 7 . As shownin FIGS. 6 and 7 , frame assembly 302 includes sides 308, 310, a base312 attached to one end of sides 308, 310, and an interface plate 306attached to an opposite end of sides 308, 310. Signal coupling elements330 are attached to each of the fiber-receiving openings formed ininterface plate 306. As explained above, coupling elements 330, whichmay comprise ferrules or connectors, are constructed and arranged tocouple an optic signal from the corresponding transmission fiber 116 toan object to be interrogated adjacent coupling elements 330, such as thecontents of a receptacle, and/or couple an optical emission from theobject into the transmission fiber 116.

Base 312 can include two openings 644, 646, each configured toaccommodate one of signal detector heads 104. A plurality offiber-positioning holes 614 is provided around each of openings 644,646. FIGS. 6 and 7 show only a portion of each of transmission fiber 116extending from interface plate 306. In the illustrated embodiment,transmission fibers 116 are connected to interface plate 306 in arectangular, multi-row arrangement, and the fiber-positioning holes 614formed in base 312 are in a circular arrangement so as to reformattransmission fibers 116 from the rectangular arrangement at the firstends of fibers 116 to a circular arrangement at the second ends offibers 116.

FIG. 8 is a perspective view of an embodiment of a frame assembly 802.Frame assembly 802 can include sides 808, 810 and a base 812 having anopening 848 formed therein with a plurality of fiber-positioning holes814 positioned around opening 848 in a generally circular configuration.An interface plate 806 is attached to sides 808, 810 of frame assembly802 at an end thereof and opposite base 812. Interface plate 806includes a plurality of coupling elements 830, e.g., ferrules orconnectors, and may include heat dissipating fins 832 disposed on a sideof interface plate 806 opposite coupling elements 830. Each couplingelement 830 corresponds to a fiber-receiving opening formed throughinterface plate 806. As can be seen in FIG. 8 , coupling elements 830are arranged in a rectangular, multi-row arrangement of six rows of fivecoupling elements 830 each. The number of openings 814 formed in base812 can correspond to the number of coupling elements 830 formed in theinterface plate 806. Thus, it can be appreciated that the frame assembly802 shown in FIG. 8 can have half the capacity of frame assembly 102shown in FIG. 1 (in some embodiments), and frame assembly 102corresponds essentially to a doubling of frame assembly 802 with asecond opening 848 and corresponding fiber-positioning holes 814surrounding opening and six additional rows of five coupling elements830 attached to interface plate 806. Frame assembly 802 could beconfigured to have the same capacity, or more or less capacity to thatof frame assembly 102 shown in FIG. 1 .

FIG. 9 shows an exemplary mapping of the spatial arrangement of fiberpositions at interface plate 806 of the frame assembly 802. As shown inFIG. 9 , interface plate 806 includes six rows, or banks, of five fiberpositions each, designated T1-T5, T6-T10, T11-T15, T16-T20, T21-T25, andT26-T30.

FIG. 10 shows an exemplary mapping of the spatial arrangement of fiberpositions of fiber-positioning holes 814 formed in base 812 of frameassembly 802. In the illustrated embodiment, 35 fiber-positioning holes814 are formed in the base 812, and are designated F1, F2, F3, F4, . . .F35, starting at the lower (six o'clock) position with respect to theopening 848.

FIG. 11 is a table showing an exemplary mapping of therectangularly-arranged interface positions T1-T30 in interface plate 806to thirty of the circularly-arranged fiber-positioning hole positionsF1-F35 in base 812. This is exemplary only; other mappings between thefiber positions in interface plate 806 and the fiber positions in base812 are contemplated. In this embodiment, the number of interfacepositions in interface plate 806 is exceeded by the number offiber-positioning holes in base 812 (e.g., 30 vs. 35). Fluorescentcalibration targets can be placed in the additional fiber-positioningholes in the base to test and/or calibrate the signal detectors ofsignal detector head 104.

FIG. 12 shows another embodiment of a thirty-fiber frame assembly 1202,including sides 1208, 1210, a base 1212 with an opening 1248,fiber-positioning openings 1214 surrounding opening 1248, and aninterface plate 1206 having coupling elements 1230 and heat dissipatingfins 1232 connected to an end of the frame assembly 1202 opposite base1212. Frame assembly 1202 is comparable to the frame assembly 802 shownin FIG. 8 and accommodates thirty transmission fibers (not shown in FIG.12 ) configured at the first ends thereof at interface plate 1206 in arectangular arrangement of six rows of five fibers each, and configuredat the second ends thereof at base 1212 in a circular arrangementdisposed within the fiber-positioning holes 1214 surrounding opening1248. Frame assembly 1202 shown in FIG. 12 differs from frame assembly802 shown in FIG. 8 in that base 1212, opening 1248, andfiber-positioning openings 1214 are substantially centered with respectto interface plate 1206. In frame assembly 802 shown in FIG. 8 , on theother hand, base 812, opening 848, and fiber-positioning openings 814are laterally offset with respect to the center of interface plate 806.

In some embodiments, the frame assembly (e.g., frame assemblies 102,302, 802, and 1202) and multicore fibers 116, according to any of theabove described embodiments, are collectively configured such that thevariation of the normalized detected intensities among all fibers 116 ateach predetermined excitation wavelength of interest is less than orequal to about ±20%. Relative to similar frame assemblies using singlecore fibers, this variation can be an improvement of about a 40% to 55%.For example, one or more of following parameters can be modified toachieve a variation of the normalized detected intensities that is lessthan or equal to about ±20%:

-   -   the length of the frame assembly (e.g., frame assemblies 102,        302, 802, and 1202)—the distance between the base and the        interface plate (e.g., a length in the range from about 130 mm        to about 160 mm);    -   the relative position between (a) the fiber-positioning holes        (e.g., holes 114, 614, 814, and 1214) of a base (e.g., bases        112, 312, 812, and 1212) of the frame assembly, and (b) the        holes (e.g., holes 128) defined by the interface plate that        receive signal coupling elements (e.g., signal coupling elements        130); and    -   the minimum bend radius of each multicore fibers 116 (e.g., a        minimum bend radius of about 5 mm or less).

Exemplary Signal Detector Heads

An embodiment of signal detector head 104 is shown in FIG. 13 . One ormore signal detector heads 104 may be attached to a frame assembly(e.g., frame assemblies 102, 302, 802, and 1202). Signal detector head104 can be configured to index one or more signal detectors intooperative positions with respect to each multicore transmission fiber116 disposed in a fiber-positioning hole (e.g., holes 114, 614, 814, and1214) of a base (e.g., bases 112, 312, 812, and 1212) of the frameassembly. That is, signal detector head 104 can be configured to indexone or more signal detectors into positions that are optically coupledto the second ends of fibers 116 attached at the base of the frameassembly. Although, signal detector head 104 is configured to be coupledto any frame assembly, including frame assemblies 102, 302, 802, and1202 described herein, for simplicity of the description, signaldetector head 104 will be described in the context of its implementationon frame assembly 102 shown in FIG. 1 .

In the embodiment shown in FIG. 13 , signal detector head 104 includes abase plate 1302 configured to be attached to base 112 of frame assembly102. Base plate 1302 can include a plurality of channels 1304 arrangedin a configuration corresponding to the spatial arrangement offiber-positioning holes 114 formed in base 112 of frame assembly 102 sothat each channel 1304 will align with a corresponding one of thefiber-positioning holes 114.

In some embodiments, signal detector head 104 can be configured to moveone or more signal detectors 1308 to sequentially place each signaldetector into an operative position with respect to each transmissionfiber 116 to detect a signal transmitted by transmission fiber 116.Signal detector head 104 can also include a movable detector carrier1306 that moves the signal detectors along a path that corresponds tothe spatial fiber arrangement of the second ends of fibers 116 attachedat base 112. In the illustrated embodiment, detector carrier 1306includes a rotating carousel that carries a plurality of signaldetectors 1308 in a circular path that corresponds to the circularspatial fiber arrangement of the second ends of fibers 116 attached atbase 112. In the illustrated embodiment, signal detector head 104 caninclude six individual signal detectors 1308. Each signal detector 1308can be mounted on a printed circuit board 1310, and each signal detector1308 can be configured to excite and detect a different optical emissionsignal or an emission signal having different characteristics. In someembodiments, signal detector head 104 includes less than or more thansix signal detectors 1308.

As will be described in further detail below, detector carrier 1306 canbe configured to move relative to base plate 1302. Signal detector head104 can also include a detector drive system 1312 configured to powermovement, e.g., rotation, of detector carrier 1306. Drive system 1312can include a drive motor 1314 supported on a motor mount portion 1316of base plate 1302. A drive belt 1318 is disposed on an output shaftwheel 1320 of motor 1314 and around a pulley wheel 1322 that is attachedto or part of detector carrier 1306. Rotation of output shaft wheel 1320of motor 1314 causes a corresponding rotation of the pulley wheel 1322and detector carrier 1306 via belt 1318.

The illustrated configuration of detector drive system 1312 isexemplary, and other mechanisms and arrangements may be employed toeffect powered movement of detector carrier 1306. For example, outputshaft wheel 1320 may comprise an output gear that directly engages gearteeth formed about the outer periphery of pulley wheel 1322, or pulleywheel 1322 could be coupled to the output shaft wheel 1320 indirectly bya gear train comprising one or more intermediate gears between theoutput shaft wheel (gear) 1320 and pulley wheel 1322. Alternatively,drive motor 1314 could be configured with its rotating output shaftattached concentrically to detector carrier 1306 and its axis ofrotation so that rotation of the output shaft by the motor causes adirect corresponding rotation of detector carrier 1306. Otherarrangements and configurations for effecting powered movement ofdetector carrier 1306 will be appreciated by persons of ordinary skillin the art.

In some embodiments, detector carrier 1306 and detector drive system1312 are configured to rotate detector carrier 1306 in a singledirection or in two directions.

Motor 1314 can be a stepper motor and may include a rotary encoder.Detector carrier 1306 may include one or more positional or statusfeedback sensors. For example, detector carrier 1306 may include a homeflag 1324 that is detected by an optical detector 1326 for indicating arotational “home” position of carrier 1306. Optical detector 1326 mayinclude a slotted optical sensor comprising an optical transmitter andreceiver in which the path between the transmitter and receiver isbroken by the passage of home flag 1324. Persons of ordinary skill inthe art will recognize, however, that other sensors for indicating ahome position may be used. Such sensors may comprise proximity sensors,magnetic sensors, capacitive sensors, etc.

A rotary connector transmits data and/or power signals between rotatingdetector carrier 1306 and signal detectors 1308 carried thereon, and anon-rotating reference environment, such as a controller and powersource as described in more detail below. In the illustrated embodiment,base 1302 of signal detector head 104 includes cylindrical housing 1328projecting upwardly from a planar portion of base 1302, and a slip ringconnector 1330 is positioned at an end of cylindrical housing 1328. Slipring connector 1330 includes a rotating element disposed insidecylindrical housing 1328 and a non-rotating element 1332, attached orotherwise coupled to non-rotating cylindrical housing 1328 by anintermediate ring 1334, to which are attached data and/or power cables1336. Slip ring connector 1330 transmits data and/or power signalsbetween rotating detector carrier 1306 and signal detectors 1308 carriedthereon, and a non-rotating reference environment, such as a controllerand power source as described in more detail below.

Further details of signal detector head 104 are shown in FIG. 14 , whichis a cross-sectional view of detector head 104 along the line 14-14 inFIG. 13 . Each signal detector 1308 includes a detector housing 1402within which are formed an excitation channel 1404 and an emissionchannel 1406, which in the illustrated embodiment are generally parallelto one another. Each signal detector 1308 can include at least oneexcitation source 1408, such as an LED, is mounted on printed circuitboard 1310 at the base of excitation channel 1404. Each signal detector1308 can include at least one emission detector 1410, such as aphotodiode, is coupled to printed circuit board 1310 and is disposedwithin emission channel 1406.

Detector carrier 1306 can also include, for example, positioned adjacentsignal detector housing 1402, a filter plate 1412 having a centralopening 1414 formed therein and defining an annulus. Within the annulus,an emission filter opening 1416 and an excitation filter opening 1418are formed in alignment with emission channel 1406 and excitationchannel 1404, respectively, of each signal detector housing 1402. Anexcitation lens 1420 and an excitation filter 1422 are disposed inexcitation opening 1418. Although a single excitation lens 1420 and asingle excitation filter 1422 are shown in FIG. 14 , signal detector1308 may include multiple excitation filters and/or multiple excitationlenses. Similarly, an emission filter 1424 and an emission lens 1426 aredisposed in emission opening 1416. Although a single emission filter1424 and a single emission lens 1426 are shown in FIG. 14 , the signaldetector 1308 may include multiple emission lenses and/or multipleemission filters.

In some embodiments, detector carrier 1306 further includes, forexample, adjacent filter plate 1412, a mirror plate 1428 having acentral opening 1430 and defining an annulus. The annulus of mirrorplate 1428 has formed therein openings aligned with emission opening1416 and excitation opening 1418 formed in filter plate 1412 for eachsignal detector 1308. In some embodiments, a mirror 1432 is disposed inmirror plate 1428 in general alignment with excitation channel 1404, anda dichroic filter 1434 is disposed in mirror plate 1428 in generalalignment with emission channel 1406. Mirror 1432 can be oriented at anangle (e.g., 45 degrees) with respect to excitation channel 1404 suchthat it can redirect a light beam.

In some embodiments, detector carrier 1306 further includes an objectivelens plate 1436 having a central opening 1438 formed therein anddefining an annulus. A lens opening 1440 is formed through the annulusof objective lens plate 1436 in general alignment with emission channel1406 of each signal detector 1308. An objective lens 1442 is disposedwithin lens opening 1440.

Base plate 1302 can be disposed adjacent objective lens plate 1436 andcan include channels 1304 formed about the perimeter thereof. Althoughbase plate 1302 and objective lens plate 1436 are depicted as abuttingone-another in FIG. 14 , it is contemplated that there can be adesignated distance, forming an air gap, between base plate 1302 andobjective lens plate 1436. Also, objective lens plate 1436 and mirrorplate 1428 are depicted as abutting one-another in FIG. 14 , it iscontemplated that there can be a designated distance, forming an airgap, between objective lens plate 1436 and mirror plate 1428.

Detector carrier 1306, having objective lens plate 1436, mirror plate1428, and filter plate 1412, and signal detectors 1308 carried thereon,are rotatable with respect to base plate 1302 so that each objectivelens 1442 associated with each of signal detectors 1308 can beselectively placed into operative alignment (i.e., optically coupled)with one of channels 1304 disposed in base plate 1302. Thus, in theillustrated embodiment having six signal detectors 1308, at any giventime, six of channels 1304 are in operative, optical alignment with oneof objective lenses 1442 and its corresponding signal detector 1308.

Operation of signal detector 1308 in an exemplary embodiment isillustrated schematically in FIG. 15 . Detector 1308 can be afluorometer that is configured to generate an excitation signal of aparticular, predetermined wavelength that is directed at the contents ofa receptacle to determine if a probe or marker having a correspondingemission signal of a known wavelength is present. When signal detectorhead 104 includes multiple fluorometers 1308 (e.g., six) eachfluorometer 1308 is configured to excite and detect an emission signalhaving a different wavelength to detect a different label associatedwith a different probe hybridized to a different target analyte. When amore frequent interrogation of a sample is desired for a particularemission signal, it may be desirable to incorporate two or morefluorometers 1308 configured to excite and detect a single emissionsignal on signal detector head 104.

An excitation signal is emitted by excitation source 1408. Excitationsource 1408, as noted above, may be an LED and may generate light at apredetermined wavelength, e.g., red, green, or blue light. Light fromsource 1408 passes through and is focused by excitation lens 1420 andthen passes through excitation filter 1422. Again, FIG. 15 is aschematic representation of signal detector 1308, and the focusingfunctionality provided by excitation lens 1420 may be affected by one ormore separate lenses disposed before and/or after the filter 1422.Similarly, the filter functionality provided by filter 1422 may beaffected by one or more individual filters disposed before and/or afterone or more lenses 1420 that provide the focusing functionality. Filter1422 may comprise a low band pass filter and a high band pass filter soas to transmit a narrow wavelength band of light therethrough. Lightpassing through excitation lens 1420 and excitation filter 1422 isreflected, e.g., laterally, by mirror 1432 toward dichroic filter 1434.Dichroic filter 1434 is configured to reflect substantially all of thelight that is within the desired excitation wavelength range towardobjective lens 1442. From objective lens 1442, light passes into atransmission fiber 116 and toward the receptacle at the opposite endthereof. The excitation signal is transmitted by transmission fiber 116to a receptacle so as to expose the contents of the receptacle to theexcitation signal.

A label that is present in the receptacle and is responsive to theexcitation signal will emit an emission signal. At least a portion ofany emission from the contents of the receptacle enters transmissionfiber 116 and passes back through objective lens 1442, which focuses theemission light toward dichroic filter 1434. Dichroic filter 1434 isconfigured to transmit light of a particular target emission wavelengthrange toward emission filter 1424 and emission lens 1426. Again, thefiltering functionality provided by emission filter 1424 may be effectedby one or more filter elements and may comprise a high band pass and lowband pass filter that together transmit a specified range of emissionwavelength that encompasses a target emission wavelength. The emissionlight is focused by the emission lens 1426, which may comprise one ormore lenses disposed before and/or after filter elements represented inFIG. 15 by emission filter 1424. Emission lens 1426 thereafter focusesthe emission light of the target wavelength at detector 1410. In oneembodiment, detector 1410, which may comprise a photodiode, willgenerate a voltage signal corresponding to the intensity of the emissionlight at the prescribed target wavelength that impinges the detector.

Returning again to FIG. 14 , a flanged tube 1443 extends through centralopening 1438 of objective lens plate 1436 and through cylindricalhousing 1328 of base plate 1302. Flanged tube 1443 includes acylindrical tube 1445 extending through central opening 1438 andcylindrical housing 1328, and a radial flange 1444 disposed withincentral opening 1430 of mirror plate 1428. Flange 1444 can be secured bysuitable fasteners, such as screws or bolts, to objective lens plate1436. Longitudinally-spaced bearing races 1446, 1448 are disposedbetween the interior of cylindrical housing 1328 and the exterior ofcylindrical tube 1445 of flanged tube 1443. Accordingly, flanged tube1443 can rotate, with detector carrier 1306, with respect to base plate1302 and cylindrical housing 1328.

Further details of an exemplary representation of slip ring connector1330 are also shown in FIG. 14 . Slip ring connector 1330 is disposed atthe end of cylindrical tube 1445 opposite radial flange 1444. As notedabove, cylindrical tube 1445 rotates with detector carrier 1306, whilecylindrical housing 1328 remains stationary with base plate 1302. Slipring connector 1330, which may comprise slip rings and brushes, includesstationary components attached or otherwise coupled to cylindricalhousing 1328 and rotating components attached or otherwise coupled torotating cylindrical tube 1445. Components 1332, 1334 representnon-rotating portion(s) of slip ring connector 1330 in which fixedcontact components, such as the brush(es), are located. Component 1450located inside tube 1445 represents rotating portion(s) of slip ringconnector 1330 that rotate with tube 1445 and in which rotating contactelements, such as the ring(s) are located. Cable 1452 represents a powerand/or data conductor(s) connecting component 1450 with printed circuitboard 1310 and which rotates with the printed circuit board 1310 andsignal detector carrier 1306.

As detector carrier 1306 rotates, each of signal detectors 1308 issequentially placed in an operative position with respect to a secondend of a different transmission fiber 116 to interrogate (i.e., measurea signal from) an emission signal source located at a first end oftransmission fiber 116. Detector carrier 1306 pauses momentarily at eachtransmission fiber 116 to permit signal detector 1308 to detect anemission signal transmitted through the transmission fiber 116. Wheresignal detector 1308 is a fluorometer, detector carrier 1306 pausesmomentarily to permit signal detector 1308 to generate an excitationsignal of a specified wavelength that is transmitted by transmissionfiber 116 to the emission signal source (receptacle) and to detectfluorescence of a specified wavelength excited by the excitation signalthat is emitted by the contents of the receptacle and transmitted by thetransmission fiber 116 to the fluorometer. Thus, in an embodiment, eachtransmission fiber 116 can be employed to transmit both an excitationsignal and the corresponding emission signal, and each signal detector1308 can be used to scan multiple transmission fibers and associatedemission signal sources.

The emission signal source associated with each transmission fiber 116is interrogated once by each signal detector 1308 for every revolutionof detector carrier 1306. Where signal detector head 104 includesmultiple signal detectors 1308 configured to detect different signals,each emission signal source is interrogated once for each differentsignal for every revolution of detector carrier 1306. Thus, in the caseof a nucleic acid diagnostic assay, which may include PCR amplification,the contents of each receptacle is interrogated for each target analytecorresponding to the different probes employed (as indicated bydifferent colored labels) once for each revolution of detector carrier1306.

In one embodiment, in which base plate 1302 of signal detector head 104includes thirty (30) fiber channels 1304 for thirty (30) transmissionfibers 116, signal detector carrier 1306 rotates one revolution everyfour (4) seconds, stopping at least ten (10) milliseconds at each fiberchannel to measure an emission signal transmitted by the associatedtransmission fiber 116. Again, if signal detector head 104 includesmultiple signal detectors 1308 (e.g., six (6) fluorometers), signaldetector head 104 will measure an emission for each of the six differentwavelengths of interest once every four (4) seconds. Accordingly, timevs. emission signal intensity data can be generated for each receptaclefor each wavelength.

When performing PCR, it is not necessary to synchronize the signal dataacquisition with the thermal cycles of the PCR process. That is, it isnot necessary that the emission signal of each receptacle be measured atthe same temperature point (e.g., about 95° C.) in the PCR cycle. Byrecording data every four seconds during the entire PCR process, asufficient number of data points will be collected at each temperatureof the PCR thermal cycle. The signal emission data is synchronized withspecific temperatures by recording a time stamp for each emission signalmeasurement and a time stamp for each temperature of the thermal cyclingrange. Thus, for example, to identify all signal measurements occurringat a temperature of about 95° C., the time stamps of the signalmeasurements are compared to the temperature time stamps correspondingto a temperature of about 95° C.

The time duration of a thermal cycle is variable, depending on the assaybeing performed. The minimum time interval is dictated by how fast thethermocycler can ramp temperatures up and down. For a cycler that canramp the vial filled with fluid from about 55° C. to about 95° C. inabout 15 seconds, an exemplary cycle would be anneal at about 55° C. forabout 25 seconds, for about 15 second from about 55. ° C. to about 95°C., denature at about 95° C. for 5 seconds, and a 15 second ramp backdown from about 95° C. to about 55° C., and then begin another cyclewith an about 25 second anneal, Thus, this exemplary anneal-denaturecycle would be about a 60 second cycle.

The control and data acquisition system of signal detector head 104,according to an embodiment, is shown schematically in FIG. 16 . As shownin FIG. 16 , detector carrier 1306 carries one or more signal detectors1308, each of which may, in one embodiment, include an excitation source1408, an excitation lens 1420, a mirror 1432, a dichroic filter 1434, anobjective lens 1442, an emission lens 1426, and an emission detector1410 as described above. Each receptacle 338 carried in, e.g., aprocessing module 334 (see FIGS. 3-5 ), is coupled to a transmissionfiber 116 that terminates in base plate 1302 of signal detector head104. Motor 1314 is mechanically coupled to detector carrier 1306 by amotor coupler 1602 to effect powered movement (e.g., rotation) ofdetector carrier 1306. A controller 1604 may be coupled to acontrollable power source 1606 and to motor 1314 for providing motorcontrol signals and receiving motor position feedback signals, e.g.,from a rotary encoder. Controller 1604 may also be coupled to otherfeedback sensors, such as the home detector 1326 for detecting arotational position of detector carrier 1306. Controller 1604 alsoprovides controlled power signals, via slip ring connector 1330, toexcitation sources 1408 rotatably carried on detector carrier 1306 andcoupled to printed circuit board 1310. The functionality of controller1604 may be provided by one controller or multiple controllers infunctional communication with each other. Moreover, one or morecontrollers, or one or more component(s) thereof, may be carried on therotating portion of detector head 104, such as on printed circuit board1310. Voltage signals from the emission detectors 1410, coupled to theprinted circuit board 1310, and other data may be carried from detectorcarrier 1306, via slip ring connector 1330, to a processor 1610 forstoring and/or analyzing the data. Alternatively, processor 1610, or oneor more component(s) thereof, may be carried on the rotating portion ofdetector head 104, such as on printed circuit board 1310.

An exemplary control configuration of signal detector head 104 isrepresented by reference number 1700 in FIG. 17 . An optics controller1702 may be provided for each detector carrier 1306, or rotor, andcoupled to printed circuit board 1310 to which the excitation sources(LED) 1408 and emission detectors (e.g., PD (photodiode)) 1410 areattached. Each optics controller 1702 may include a microcontroller1704, e.g., a PIC18F-series microcontroller available from MicrochipTechnology Inc., an analog to digital converter 1706, and an integratedamplifier 1708 (e.g., one for each emission detector (PD) 1410). Aconstant current driver 1710 (e.g. one for each excitation source 1408)is controlled by the microcontroller 1712 and generates control signals(e.g., controlled power) to excitation source 1408. Controller 1702receives power at point 1714 (e.g., 24 V) from slip ring connector 1330and can include a serial data link RS-485 914 for commutations betweenthe controller 1702 and slip ring connector 1330.

An exemplary control configuration 1700 may include a motion controller1716 for each detector drive system 1312 (see FIG. 13 ). At 1718, motioncontroller 1716 receives power, e.g., 24 VDC, 40 watts from controllablepower source 1606 (see FIG. 15 ), that is transmitted to opticscontroller 1702 via slip ring connector 1330. Motion controller 1716 maycommunicate with an external controller via a serial data link 1720. Inone embodiment, controller 1716 communicates with a controller of thethermocycler to synchronize operation of signal detector head 104 withoperation of the thermocycler. Controller 1716 may include a serial datalink RS-485 1722 for communications between the controller 1716 and slipring connector 1330. Controller 1716 may further include amicrocontroller 1712, e.g., a PIC18F-series microcontroller availablefrom Microchip Technology Inc. and a PMD chip set 1724, which is can bea motor controller to control stepper motor 1314. A stepper motor driver1726 can be controlled by microcontroller 1712, and generates motorcontrol signals for motor 1314 of optics rotor (i.e., detector drive). Aslotted optical sensor input 1728 receives signals from the home flagdetector 1326 and communicates such signals to microcontroller 1712.

An alternative embodiment of a signal detector head embodying aspects ofthe present disclosure is indicated by reference number 1800 in FIGS. 17and 18 . Signal detector head 1800 includes a filter wheel 1802 and acamera 1804 oriented in a radial focal direction with respect to filterwheel 1802. Signal detector head 1800 can employ camera 1804 to image aplurality of bundled fibers 116 to detect a signal transmitted by eachfiber 116. Filter wheel 1802 can be indexed to selectively couple eachof one or more excitation sources and emission filters with the fiberbundle and camera 1804 to direct an excitation signal of a specifiedcharacteristic, e.g., wavelength, to fibers 116 of the fiber bundle andto direct emission signals of a specified characteristic, e.g.,wavelength, from fibers 116 of fiber bundle to the camera 1804.

More particularly, signal detector head 1800 includes a filter wheel1802 that comprises a body 1806. Body 1806 can be configured to rotateabout a central axis. Signal detector head 1800 can include a motor 1808is coupled to filter wheel 1802 by a transmission 1902 to effect poweredrotation of filter wheel 1802. Transmission 1902 may comprise anysuitable transmission means for transmitting the rotation of motor 1808to filter wheel 1802. Exemplary transmissions include inter-engagedgears, belts, and pulleys, and an output shaft of the motor 1808directly attached to body 1806, etc. Motor 1808 may be a stepper motorto provide precise motion control, and may further include a rotaryencoder. Filter wheel 1802 may further include a home flag forindicating one or more specified rotational positions of filter wheel1802. Suitable home flags include slotted optical sensors, magneticsensors, capacitive sensors, etc. A fiber bundle 1810 includes aplurality of fibers 116 fixed at the first ends thereof with respect tofilter wheel 1802, e.g., to a fixed plate 1812 located adjacent tofilter wheel 1802, by a fiber mounting block 1814. The second ends ofthe respective fibers 116 are coupled to respective signal sourcespositioned in a first specified arrangement, and may include receptacles(such as receptacles 338) positioned in a rectangular arrangement.

Filter wheel 1802 includes one or more optics channels 1904 and ismovable so as to selectively index each optics channel 1904 into anoperative, optical communication with the fiber bundle 1810 and camera1804. Each optics channel 1904 includes an excitation channel 1906formed in an axial direction within body 1806 of index wheel 1802 fortransmitting an excitation signal to fiber bundle 1810 and an emissionchannel 1908 extending radially from excitation channel 1906 to a radialopening on the outer periphery of filter wheel 1802.

An excitation source 1910, e.g., a bright light LED, is disposed withinthe excitation channel 1906. The excitations sources 1910 of all theemission channels 1908 may be connected to a printed circuit board 1816.One or more lenses 1912 and one or more excitation filters 1914 arepositioned within excitation channel 1906 to condition light emitted bysource 1910. Each optics channel 1904 may be configured to generate andtransmit an excitation signal of a specified wavelength. In such anembodiment, filter(s) 1914 are configured to transmit light at thedesired wavelength.

Each channel 1904 includes a dichroic filter 1916 configured to transmitthat portion of the excitation signal that is at or near the prescribedexcitation wavelength.

When the optics channel 1904 is in optical communication with the fiberbundle 1810—such as by rotating the filter wheel 1802 until opticschannel 1904 is aligned with a fiber channel 1820 within, or adjacentto, which fiber bundle 1810 is secured—an objective lens 1920 transmitsthe excitation signal from excitation channel 1906 into each fiber 116of fiber bundle 1810. Emissions from the emissions sources at theopposite ends of fibers 116 are transmitted by each fiber of fiberbundle 1810 back through objective lens 1920 and into optic channel1904. Dichroic filter 1916 may be configured to reflect light of aspecified emission wavelength. Thus, that portion of the emission lighttransmitted by fiber bundle 1810 into optics channel 1904 that is at thespecified emission wavelength is reflected by the dichroic filter 1916into the emission channel 1908.

An emission filter 1922 is disposed within the emission channel 1908 andis configured to transmit light having the desired emission wavelength.The emission channel 1908 terminates at a radial opening 1818 formedabout the outer periphery of body 1806. In an embodiment, optics channel1904 is oriented with respect to camera 1804 such that an optic channel1904 that is in optical communication with fiber bundle 1810 is also inoptical communication with camera 1804.

When optics channel 1904 is an operative position with respect to camera1804, the radial opening 1818 of emission channel 1908 is aligned withimage relay optics 1924 that transmit emission light from emissionchannel 1908 into camera 1804. Camera 1804 then images the emissionsignals transmitted by all fibers 116 in fiber bundle 1810 at once. Todetermine the signal transmitted by each fiber—and thus the signalemitted by the signal emission source associated with the fiber—thepixels of the camera's pixel matrix are mapped to the fiber locationswithin fiber bundle 1810 to identify the one or more pixels of the pixelarray that correspond to each fiber 116. By interrogating the signalimaged at each pixel or group of pixels associated with a fiber, thesignal (e.g. the color (wavelength) and/or intensity) of the emissionsignal transmitted by that fiber can be determined.

Suitable cameras include CMOS camera such as the IDS UI-5490HE camera orCCD camera such as the Lumenera LW11059 or the Allied GE4900.Preferably, the camera has at least 10 megapixels and has a high framerate.

In an embodiment, the filter wheel 1802 includes multiple (e.g., 3 to 6)optics channels 1904, each configured to excite and detect an emissionof a different wavelength or other specific, distinguishingcharacteristic. Thus by rotating filter wheel 1802 to index each opticschannel 1904 with respect to fiber bundle 1810 and camera 1804, signalsof each distinguishing characteristic can be measure from all fibers andassociated signal emission sources.

It will be appreciated that the signal detector head may include one ormore additional cameras positioned and be coupled to one or moreadditional fiber bundles to permit simultaneous imaging of the multiplefiber bundles.

Exemplary Optical Misalignment Diagnostic Methods

Exemplary methods of diagnosing an optical misalignment between (a) anoptical component (e.g., channel, lens, filter, source, detector) of anoptical signal detector head and an end of fiber 116 will now bedescribed. Again, fiber 116 can be a multicore fiber having a pluralityof cores 118 in which the relative spatial arrangement of cores 118 ispreserved between the two ends of fiber 116. Such a multicore fiber 116can be used to efficiently diagnose (i.e., determine the presence orabsence of) an optical misalignment between various optical componentsof optical signal detector head and fiber 116. Any of the belowdescribed exemplary methods can be used with any frame assembly,including frame assemblies 102, 302, 802, and 1202 described herein, butfor simplicity of the description, these methods will be described inthe context of its implementation on frame assembly 102 shown in FIG. 1.

In some embodiments, an optical misalignment between (a) objective lens1442 of signal detector 1308 or channel 1304 of base plate 1302 and (b)the end of fiber 116 coupled to base 112 can be diagnosed. ReferencingFIGS. 14 and 15 , the diagnostic method can include generating lightusing excitation source 1408 of signal detector 1308. The generatedlight passes through lens 1420 and filter 1422, reflects off mirror1432, then reflects off dichroic filter 1434, exits objective lens 1442,and passes through channel 1304. The end of multicore fiber 116 (whichis attached to base 112 of frame assembly 102) that is adjacent andoptically coupled to channel 1304 and objective lens 1442 receives thelight, and fiber 116 transmits the light to toward the end of fiber 116attached to interface plate 106. This transmission generates an lightpattern or image at the other end of fiber 116 attached to interfaceplate 106. This pattern can be generated either on fiber 116, itself, oron a signal coupling device 130 optically coupled to fiber 116.

An optical misalignment between a component of signal detector 104(e.g., objective lens 1442 of signal detector 1308 or channel 1304) andthe end of fiber 116 coupled to base 102 and optically coupled to signaldetector 104 can be diagnosed based on the symmetry (or asymmetry) ofthe resulting intensity pattern of the light pattern or image formed atthe other end of multicore fiber 116. If the end of multicore fiber 116(attached to base 112) adjacent and optically coupled to objective lens1442 is optically aligned with objective lens 1442 and channel 1304, theresulting intensity pattern at the other end of multicore fiber 116(formed directly on fiber 116, itself, or on signal coupling device 130)will be substantially symmetric. In the context of this application,symmetric means that the resulting pattern is symmetric about twoperpendicular axes intersecting at the center of the pattern, andasymmetric means that the resulting pattern is not symmetric about oneor both of such axes. FIG. 20 illustrates an exemplary symmetricintensity pattern of the end of multicore fiber 116. The cores 118Ashaded with the light gray represent cores transmitting light with thegreatest intensity. Cores 118A form a substantially circular, symmetricshape. The cores 118B shaded with a medium gray represent corestransmitting light with a slightly lower intensity than cores 118A atthe center of the intensity pattern. These medium gray cores 118B form asubstantially annular, symmetric shape. Collectively, cores 118A andcores 118B form a symmetric intensity pattern. This symmetric patternshown in FIG. 20 is only exemplary, and other symmetric patterns may beformed. For example, the size, shape, and location of cores 118A and118B may vary. And for example, there may be more than or less than twogroups of cores with noticeably different intensities.

If the end of multicore fiber 116 adjacent and optically coupled toobjective lens 1442 is optically misaligned relative to objective lens1442, the resulting intensity pattern at the other end of multicorefiber 116 will be asymmetric. FIG. 21 illustrates an exemplaryasymmetric resulting intensity pattern at the other end of multicorefiber 116 (formed directly on fiber 116, itself, or on signal couplingdevice 130). The cores 118A shaded with light gray represent corestransmitting light with the greatest intensity. These cores 118A form asubstantially trapezoidal shape at the bottom of the pattern. The cores118B shaded with medium gray represent cores transmitting light with alower intensity than cores 118A. These cores 118B form a substantiallyrectangular shape. The cores 118C shaded with dark gray represent corestransmitting light with a lower intensity than both cores 118A and 118B.These cores 118B form a substantially crescent-like shape at the top ofthe pattern. Collectively, the resulting intensity pattern formed bycores 118A, 118B, and 118C is asymmetric. This asymmetric pattern shownin FIG. 21 is only exemplary, and other asymmetric patterns may beformed. For example, the size, shape, and location of cores 118A, 118B,and 118C may vary. And for example, there may be more than or less thanthree groups of cores with noticeably different intensities.

Notably, the use of varying shades of gray in FIGS. 20 and 21 is forillustrative purposes only. In reality, the resulting color of cores 118can be colors other than gray, for example, white, red, blue, green,orange, etc.

The symmetry or asymmetry of the resulting intensity pattern can bedetermined either manually or automatically.

In some manual embodiments, a person can visually inspect the imageformed at the end of multicore fiber 116 (formed directly on fiber 116,itself, or on signal coupling device 130 at that end) to determinesymmetry or asymmetry of the resulting intensity pattern. In some manualembodiments, this visually inspection can occur without the use of anyother tools or devices. In other embodiments, this visually inspectionincludes using a magnifier to generate a magnified image of the end ofthe multicore fiber 116. Based on the visual inspection of the magnifiedimage, the person can determine the symmetry or asymmetry of theresulting intensity pattern. The magnifier can be, for example, anelectronic magnifying system having a camera system that acquires animage of the intensity pattern, and a display device that displays amagnified image of the acquired intensity pattern image. Or for example,the magnifier can be a magnifying glass.

In some automated embodiments, a camera system is used to automaticallydetermine the symmetry or asymmetry of the resulting intensity pattern.The imaging device system can include, for example, a camera thatacquires an image of the resulting intensity pattern at the end ofmulticore fiber 116. Suitable cameras include CMOS cameras and CCDcameras. The acquired image can then be processed to determine thesymmetry or asymmetry of the resulting intensity pattern. For example,the pixels of the acquired image can be interrogated, eitherindividually or in groups, to determine the symmetry or asymmetry of theresulting intensity pattern. In some embodiments, the camera system usedfor automatic determination is part of the sample assay instrument. Inother embodiments, the camera system is a separate from the sample assayinstrument.

Again, if asymmetry of the resulting intensity pattern is detected, theend of multicore fiber 116 adjacent and optically coupled to objectivelens 1442 is optically misaligned relative to objective lens 1442 andchannel 1304.

In some embodiments, the relative position of the end of multicore fiber116 near and optically coupled to objective lens 1442 can be adjusted toreduce or eliminate the optical misalignment indicated by the asymmetricintensity pattern. The direction and magnitude of the relative positionadjustment for correcting the optical misalignment can be determinedbased on the resulting asymmetric intensity pattern. That is, theresulting asymmetric intensity pattern can directly show the magnitudeand direction of the misalignment because the relative spatialarrangement of cores 118 of fiber 116 is preserved between the two endsof fiber 116. For example, referencing FIG. 21 , the location of thecores 118A having the greatest intensity at the bottom of the patternindicates that the center of the optical element of the signal detector(e.g., the center of objective lens 1442 of signal detector 1308) isoffset below (within the plane of the page as a reference) thedetector-side end of fiber 116. Accordingly, if the signal detector ismoved up (within the plane of the page as a reference) relative to thedetector-side end of fiber 116 by about a half diameter of fiber 116,the optical misalignment will be reduced or eliminated. This reductionor elimination of misalignment after the positional adjustment can beconfirmed by repeating the above steps and analyzing the symmetry orasymmetry of the resulting intensity pattern.

In some embodiments, signal detection head 104 and frame assembly 102(to which fiber 116 is attached) are configured to allow for suchrelative position adjustment. For example, signal detection head 104 andframe assembly 102 can be configured to be securely coupled to eachother at a plurality of different relative positions. In someembodiments, one of signal detection head 104 and frame assembly 102defines an elongated channel that can receive a fastener or pin coupledto the other of the signal detection head 104 and frame assembly 102.Due to the elongation of the channel, the fastener or pin can slidewithin the channel to allow for the relative position adjustment betweenthe end of multicore fiber 116 near (and frame assembly 102) andoptically coupled objective lens 1442 of signal detection head 104. Oncethe desired relative position is achieved (i.e., when the end ofmulticore fiber 116 adjacent and optically coupled objective lens 1442are optically aligned), the signal detection head 104 and frame assembly102 can be securely coupled together in a fixed manner (e.g., bytightening a fastener that thereby prevents relative movement).

In some embodiments, the above described diagnostic method can beperformed during the manufacturing stage of a sample assay instrumentthat uses the signal detector and optical fiber. That is, the method isperformed before the sample assay instrument is received by theend-user. In other embodiments, the above described diagnostic methodcan be performed as part of a maintenance routine or whiletroubleshooting a problem at the customer site.

Hardware and Software

Aspects of the disclosure are implemented via control and computinghardware components, user-created software, data input components, anddata output components. Hardware components include computing andcontrol modules (e.g., system controller(s)), such as microprocessorsand computers, configured to effect computational and/or control stepsby receiving one or more input values, executing one or more algorithmsstored on non-transitory machine-readable media (e.g., software) thatprovide instruction for manipulating or otherwise acting on the inputvalues, and output one or more output values. Such outputs may bedisplayed or otherwise indicated to a user for providing information tothe user, for example information as to the status of the instrument ora process being performed thereby, or such outputs may comprise inputsto other processes and/or control algorithms. Data input componentscomprise elements by which data is input for use by the control andcomputing hardware components. Such data inputs may comprise positionssensors, motor encoders, as well as manual input elements, such askeyboards, touch screens, microphones, switches, manually-operatedscanners, etc. Data output components may comprise hard drives or otherstorage media, monitors, printers, indicator lights, or audible signalelements (e.g., buzzer, horn, bell, etc.).

Software comprises instructions stored on non-transitorycomputer-readable media which, when executed by the control andcomputing hardware, cause the control and computing hardware to performone or more automated or semi-automated processes.

While the present disclosure has been described and shown inconsiderable detail with reference to certain illustrative embodiments,including various combinations and sub-combinations of features, thoseskilled in the art will readily appreciate other embodiments andvariations and modifications thereof as encompassed within the scope ofthe present invention. Moreover, the descriptions of such embodiments,combinations, and sub-combinations is not intended to convey that thedisclosures require features or combinations of features other thanthose expressly recited in the claims. Accordingly, the presentinvention is deemed to include all modifications and variationsencompassed within the spirit and scope of the following appendedclaims.

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofexample, and not limitation. It will be apparent to persons skilled inthe relevant art that various changes in form and detail can be madetherein without departing from the spirit and scope of the invention.

The present invention has been described above with the aid offunctional building blocks and method steps illustrating the performanceof specified functions and relationships thereof. The boundaries ofthese functional building blocks and method steps have been arbitrarilydefined herein for the convenience of the description. Alternateboundaries can be defined so long as the specified functions andrelationships thereof are appropriately performed. Any such alternateboundaries are thus within the scope and spirit of the claimedinvention. One skilled in the art will recognize that these functionalbuilding blocks can be implemented by discrete components, applicationspecific integrated circuits, processors executing appropriate softwareand the like or any combination thereof. Thus, the breadth and scope ofthe present invention should not be limited by any of theabove-described exemplary embodiments, but should be defined only inaccordance with the following claims and their equivalents.

Although specific embodiments are described above, as a person skilledin the art would recognize, many variations of the disclosed embodimentsare possible, and therefore, within the scope of this disclosure.

What is claimed is:
 1. An apparatus for detecting an optical signalemission from a plurality of signal emission sources, comprising: aplurality of signal transmission fibers each comprising a plurality ofcores having a first spatial core arrangement at a first end and asecond spatial core arrangement at a second end that is the same as thefirst spatial core arrangement, each first end being configured to beoptically coupled to a respective signal emission source, and each fiberbeing configured to transmit an optical signal emitted between the firstend and the second end; a frame assembly securing the first ends of theplurality of signal transmission fibers in a first spatial fiberarrangement corresponding to a spatial arrangement of the signalemission sources, and securing the second ends of the plurality ofsignal transmission fibers in a second spatial fiber arrangementdifferent from the first spatial fiber arrangement; at least one signaldetector configured to detect an optical signal emitted by each signalemission source; and a camera system configured to: (1) acquire an imageof an intensity pattern of an optical signal emitted by the at least onesignal detector and transmitted from the first end of at least one ofthe signal transmission fibers to a second end of the at least one ofthe signal transmission fibers, and (2) determine whether the acquiredimage of the intensity pattern of the transmitted optical signal issymmetric or asymmetric.
 2. The apparatus of claim 1, wherein: the atleast one signal detector comprises a plurality of signal detectors,wherein each signal detector is configured to generate an excitationlight of a different predetermined wavelength and to detect light of adifferent predetermined emission wavelength; and the apparatus furthercomprises a signal detector carrier having mounted thereon the pluralityof signal detectors, the signal detector carrier being configured tomove such that each signal detector is sequentially and opticallycoupled to the second ends of the plurality of signal transmissionfibers.
 3. The apparatus of claim 1, wherein the first spatial fiberarrangement is rectangular and comprises two or more rows, each rowincluding two or more of the first ends of the signal transmissionfibers.
 4. The apparatus of claim 1, wherein the second spatial fiberarrangement comprises one or more circles each comprising a plurality ofsecond ends of the plurality of signal transmission fibers.
 5. Theapparatus of claim 4, wherein the signal detector carrier comprises arotatable carousel configured to move the one or more signal detectorsalong a circular path corresponding to the one or more circles of thesecond spatial fiber arrangement.
 6. The apparatus of claim 1, whereinthe frame assembly comprises: an interface plate securing the first endsof the plurality of signal transmission fibers in the first spatialfiber arrangement; and a base, spaced apart from the interface plate,securing the second ends of the plurality of signal transmission fibersin the second spatial arrangement.
 7. The apparatus of claim 1, furthercomprising a plurality of signal coupling elements, each beingoperatively optically coupled to a respective first end of each signaltransmission fiber.
 8. The apparatus of claim 1, wherein a minimum bendradius of the plurality of signal transmission fibers is equal to orless than about 10 mm.
 9. The apparatus of claim 8, wherein the minimumbend radius of the plurality of signal transmission fibers is equal toor less than about 5 mm.
 10. The apparatus of claim 1, wherein theplurality of cores comprises more than 15 cores.
 11. The apparatus ofclaim 10, wherein the plurality of cores comprises at least 37 cores.12. The apparatus of claim 1, wherein: each core of the plurality ofcores comprises polymethyl methacrylate (PMMA); and each core of theplurality of cores is encased by a cladding comprising a fluorinatedpolymer.
 13. The apparatus of claim 1, wherein each core has anon-circular cross-sectional shape.
 14. A method of diagnosing anoptical misalignment between a signal detector and a first end of asignal transmission fiber, the method comprising the steps of: emittingan optical signal from the signal detector; transmitting the emittedoptical signal from the first end of the signal transmission fiber to asecond end the signal transmission fiber; determining whether anintensity pattern of the transmitted optical signal is symmetric orasymmetric, wherein a symmetric intensity pattern indicates that thesignal detector and the first end of signal transmission fiber areoptically aligned, and wherein an asymmetric intensity pattern indicatesthat the signal detector and the first end of the signal transmissionfiber are optically misaligned.
 15. The method of claim 14, wherein thedetermining step is manual.
 16. The method of claim 15, wherein thedetermining step comprises visually inspecting the intensity pattern.17. The method of claim 16, wherein the visually inspecting stepcomprises using a magnifier that generates a magnified image of theintensity pattern.
 18. The method of claim 17, wherein the magnifiercomprises a magnifying glass.
 19. The method of claim 17, wherein themagnifier comprise a camera system comprising a camera and a displaythat displays the magnified image.
 20. The method of claim 14, whereinthe determining step is automatic.
 21. The method of claim 20, whereinthe determining step comprises: acquiring an image of the intensitypattern; and automatically analyzing the acquired image to determinewhether the intensity pattern of the transmitted optical signal issymmetric or asymmetric.
 22. The method of claim 14, further comprising,when the intensity pattern of the transmitted optical signal isasymmetric, adjusting the relative position between the signal detectorand the first end of the signal transmission fiber.
 23. The method ofclaim 22, wherein at least one of a magnitude and a direction of arelative position adjustment between the signal detector and the firstend of the signal transmission fiber is determined based on theintensity pattern.
 24. The method of claim 14, wherein the emitting,transmitting, and determining steps occur during the manufacturingprocess of a sample assay instrument comprising the signal detector andthe signal transmission fiber.
 25. The method of claim 14, wherein theemitting, transmitting, and determining steps occur during routinemaintenance of a sample assay instrument comprising the signal detectorand the signal transmission fiber, or while trouble shooting a problemwith the diagnostic instrument after manufacturing.